# Project 2: Defining and exploiting genetic dependencies in complex karyotype AML

> **NIH NIH P50** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $367,707

## Abstract

ABSTRACT
Complex karyotype acute myeloid leukemia (CK AML) is defined by the presence of 3 or more detectable
cytogenetic abnormalities and has one of the least favorable prognoses of any leukemia genotype. Genomic
characterization indicates that this disease lacks conventional druggable oncoproteins, but instead is
characterized by a set of recurrent segmental deletions and mutations in the TP53 tumor suppressor gene, the
latter of which are absent from normal karyotype AML and confer resistance to standard chemotherapies. To
better characterize the pathogenesis of CK AML and to develop new strategies to treat this disease, we will
exhaustively analyze the genomes of a large cohort of CK AML samples using a new low-cost, high-resolution
platform optimized in our group called “digital karyotyping”. These molecular features will be correlated with
patient outcomes data, and used to generate murine and human models that accurately recapitulate CK AML-
specific features. We will use these models to test a new therapeutic strategy for countering the pro-tumorigenic
effects of p53 loss. This concept builds on preliminary data showing that p53 loss can perturb cellular metabolism
in a manner that alters gene expression and drives aberrant self-renewal, and that reversing these effects with
small molecule inhibitors can drive differentiation of p53-deficient AML. Specifically, we have found that p53
mutations reduce levels of the metabolite aKG, producing similar effects of oncogenic IDH1/2 mutant proteins
that have proven to be drug targets in other sub-types of AML. In models studied to date, the tumor suppressive
effects of p53 are recapitulated by inhibiting the TCA enzyme 2-oxoglutarate dehydrogenase (OGDH) and, as
such, we consider OGDH a prime candidate for validation and development in CK AML. Successful completion
of the proposed research will produce a detailed understanding of the genetic changes that accompany CK AML
and allow for more faithful modeling of human disease. In addition, we hypothesize that oxoglutarate
dehydrogenase (OGDH) a promising therapeutic target for the treatment of CK AML. Validating our novel drug
target will pave the way for clinical trials in this indication. Given the paucity of effective therapeutic options for
patients with CK AML, the proposed studies address an urgent, unmet clinical need.

## Key facts

- **NIH application ID:** 10474281
- **Project number:** 5P50CA254838-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** SCOTT W. LOWE
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $367,707
- **Award type:** 5
- **Project period:** 2021-08-24 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10474281

## Citation

> US National Institutes of Health, RePORTER application 10474281, Project 2: Defining and exploiting genetic dependencies in complex karyotype AML (5P50CA254838-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10474281. Licensed CC0.

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